Alzheimer Disease: Esselmann H

Weih M, Abu-Omar K, Esselmann H, Gelbrich G, Lewczuk P, Rütten A, Wiltfang J, Kornhuber J. · Psychiatrische und Psychotherapeutische Klinik, Universitätsklinikum Erlangen. · Fortschr Neurol Psychiatr. · Pubmed #19283649 No free full text.

Abstract: There is accumulating evidence from animal and epidemiologic studies that physical exercise is neuroprotective in healthy animals and humans and can prevent cognitive decline in chronic neurodegenerative processes like Alzheimer's dementia. However, data from well-designed interventional, randomized non-pharmacologic trials is lacking in contrast to other areas of medicine like prevention of hypertension, diabetes or the antipsychotic-associated metabolic syndrome. The demonstration of a potential positive effect of physical exercise on preventing dementia using a controlled study design would represent a significant progress in the prevention of dementia and public health, especially as long as other treatments for dementia prevention are lacking.

Wiltfang J, Lewczuk P, Riederer P, Grünblatt E, Hock C, Scheltens P, Hampel H, Vanderstichele H, Iqbal K, Galasko D, Lannfelt L, Otto M, Esselmann H, Henkel AW, Kornhuber J, Blennow K. · Molecular Neurobiology Lab, Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. · World J Biol Psychiatry. · Pubmed #16156480 No free full text.

Abstract: Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Abeta peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.

Wiltfang J, Esselmann H, Maler JM, Bleich S, Hüther G, Kornhuber J. · Department of Psychiatry, Georg August University, Göttingen, Germany. · Gerontology. · Pubmed #11287729 No free full text.

Abstract: Over the past few years, molecular biological research has considerably deepened our understanding of the pathophysiological basis of Alzheimer's dementia (AD). Although different genetic origins of the disease have been identified, all of the findings point to a common terminal sequence in familial AD. This consists of an increased production of beta-amyloid peptides from beta-amyloid precursor protein. For the cases of sporadic AD, which far outweigh the number of cases of familial AD, an impaired catabolism of the beta-amyloid peptides may also be pathophysiologically decisive according to the latest findings. Research into the molecular level of AD makes it possible to identify points of attack for rational drug treatment of the disease, while molecular markers of AD are increasingly being used as a part of early and differential neurochemical diagnostics.

Lewczuk P, Esselmann H, Groemer TW, Bibl M, Maler JM, Steinacker P, Otto M, Kornhuber J, Wiltfang J. · Department of Psychiatry and Psychotherapy (PL, TWG, JMM, JK, JW), University of Erlangen-Nuremberg, Erlangen, Germany. · Biol Psychiatry. · Pubmed #15023581 No free full text.

Abstract: BACKGROUND: The advent of new therapeutic avenues for Alzheimer's disease (AD) calls for an improved early and differential diagnosis. METHODS: With surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), cerebrospinal fluid from patients with AD (n = 10) and nondemented control subjects (n = 9) was studied. RESULTS: Molecular mass signals were observed corresponding to three novel amyloid beta (Abeta) peptides that have not previously been described, in addition to those previously known, with molecular masses of 4525.1 d, 4846.8 d, and 7755.8 d. The signal-to-noise ratios (S/NR) of Abeta(4525.1) and Abeta(7758.8+2H) were significantly decreased in AD [Abeta(4525.1): median 2.2 and 4.3 in AD and control subjects, respectively, p <.01; Abeta(7758.8+2H): median 1.0 and 14.0 in AD and control subjects, respectively, p <.01], whereas the S/NR of Abeta(4846.8) was significantly increased in AD (median 3.6 and 2.5 in AD and control subjects, respectively, p <.05). The S/NR of two known AD biomarkers, Abeta1-42 and Abeta1-40, expectedly turned out to be significantly decreased (p <.01) and unaltered in AD, respectively. A moderate and highly significant correlation was observed between S/NR of Abeta1-42 and Abeta42 concentration as measured with enzyme-linked immunosorbent assay (R =.67, p <.01). CONCLUSIONS: We report evidence of three novel amyloid beta peptides that might play an important role in the diagnosis and pathophysiology of Alzheimer's disease.

Serneels L, Van Biervliet J, Craessaerts K, Dejaegere T, Horré K, Van Houtvin T, Esselmann H, Paul S, Schäfer MK, Berezovska O, Hyman BT, Sprangers B, Sciot R, Moons L, Jucker M, Yang Z, May PC, Karran E, Wiltfang J, D'Hooge R, De Strooper B. · Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium. · Science. · Pubmed #19299585 No free full text.

Abstract: The gamma-secretase complex plays a role in Alzheimer's disease and cancer progression. The development of clinically useful inhibitors, however, is complicated by the role of the gamma-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different gamma-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B gamma-secretase in a mouse Alzheimer's disease model led to improvements of Alzheimer's disease-relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total gamma-secretase activity in the human brain, and thus specific targeting of Aph1B-containing gamma-secretase complexes may help generate less toxic therapies for Alzheimer's disease.

Welge V, Fiege O, Lewczuk P, Mollenhauer B, Esselmann H, Klafki HW, Wolf S, Trenkwalder C, Otto M, Kornhuber J, Wiltfang J, Bibl M. · Klinik für Psychiatrie und Psychotherapie, Universität Duisburg-Essen, Rheinische Kliniken Essen, Essen, Germany. · J Neural Transm. · Pubmed #19142572 No free full text.

Abstract: Cerebrospinal fluid (CSF) concentrations of amyloid-beta (Abeta) 1-38, 1-40, 1-42, total-tau and phospho-tau in samples from 156 patients with Alzheimer's disease (AD) (n = 44), depressive cognitive complainers (DCC, n = 25) and various other forms of non-Alzheimer dementias (NAD, n = 87) were analyzed by electrochemiluminescence and enzyme linked immunosorbent assay, respectively. A significant decrease of CSF Abeta1-42 was the most powerful single marker for differentiation of AD from DCC, yielding accuracies of beyond 85%. Increased p-tau and the ratio Abeta1-42/Abeta1-38 yielded accuracies of beyond 80 and 85%, respectively, to discriminate AD versus NAD. Combining p-tau with Abeta1-42/Abeta1-38 resulted in a sensitivity of 94% for detection of AD and 85% specificity for excluding NAD. Decreased CSF Abeta1-42 represents a core biomarker for AD. The lack of specificity for exclusion of NAD can be most effectively compensated by the ratio Abeta1-42/Abeta1-38. The ratio Abeta1-42/Abeta1-38/p-tau powerfully discriminates AD versus NAD and fulfils the accuracy requirements for an applicable screening and differential diagnostic AD biomarker.

Maler JM, Spitzer P, Klafki HW, Esselmann H, Lewczuk P, Kornhuber J, Herrmann M, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany. · J Neuroimmunol. · Pubmed #18824266 No free full text.

Abstract: The presence of cells of the mononuclear phagocyte lineage surrounding neuritic and vascular beta-amyloid (Abeta) plaques is a hallmark of Alzheimer's disease (AD) neuropathology. The fractional Abeta peptide patterns released by human mononuclear phagocyte (MNP), lymphocyte and PBMC cultures were assessed by Abeta-SDS-PAGE/immunoblot and compared with the Abeta patterns in neuronal supernatants, in cerebrospinal fluid (CSF), and plasma. MNP released substantial amounts of Abeta peptides and the Abeta pattern contrasted with that in neuronal supernatants, CSF and plasma by reduced Abeta(1-42) and increased proportions of N-truncated Abeta species. MNP derived from early AD patients released significantly more total Abeta peptides than age-matched controls. The proportion of Abeta(1-42) was not altered.

Mamo JC, Jian L, James AP, Flicker L, Esselmann H, Wiltfang J. · Division of Health Sciences, Curtin University of Technology and ATN Centre for Metabolic Health and Fitness. · Ann Clin Biochem. · Pubmed #18583625 No free full text.

Abstract: BACKGROUND: Plasma amyloid beta-peptide (Abeta) can compromise the blood-brain barrier, contributing to cerebrovascular alterations and amyloid angiopathy in Alzheimer's disease (AD). The objectives of this study were to investigate the distribution of lipoprotein-bound plasma-Abeta isoforms. METHODS: This involved a case-control study of subjects with AD or amnestic mild cognitive impairment (MCI) versus controls. Lipoprotein Abeta distribution was determined in fasted plasma. For assessment of chylomicron homeostasis in the postabsorptive state, subjects were bled 4 h after a low-fat meal. The main outcome measures were plasma lipoprotein Abeta isoform distribution and lipid homeostasis. RESULTS: We found the majority of plasma Abeta to be associated with triglyceride-rich lipoproteins (TRLs) encompassing chylomicrons, VLDL and IDL. For all lipoprotein groups, Abeta1-40 was the predominant isoform, accounting for approximately 50% of the total. Thereafter, equivalent amounts of the isoforms 1-42, 2-40, 1-38, 1-37 and 1-39 were found. Abeta1-37, Abeta1-38 and Abeta2-40 isoforms were significantly enriched within the TRL fraction of AD/MCI subjects and similar trends were observed for isoforms Abeta1-39, Abeta1-40 and Abeta1-42. Lipoprotein-Abeta was inversely associated with plasma total- and LDL cholesterol. AD/MCI subjects were not dyslipidaemic, however, there was evidence of accumulation of chylomicrons in the postabsorptive state. CONCLUSIONS: Our data show that Abeta was found to be associated with plasma lipoproteins, especially those enriched with triglyceride. We find that Abeta may be increased in normolipidaemic AD subjects, commensurate with possible disturbances in postprandial lipoprotein homeostasis.

Maler JM, Spitzer P, Klafki HW, Esselmann H, Bibl M, Lewczuk P, Kornhuber J, Herrmann M, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany. · Brain Behav Immun. · Pubmed #18511234 No free full text.

Abstract: Cells of the mononuclear phagocyte system are closely associated with vascular and neuritic beta-amyloid deposits in Alzheimer's disease. Using one-dimensional and newly developed two-dimensional Abeta-SDS-PAGE Western immunoblot techniques (1D/2D-Abeta-WIB) we investigated the patterns of Abeta peptides released by primary non-adherent and adherence-activated human mononuclear phagocytes in vitro. An overall increase of total released Abeta peptides (Abeta(total)) was observed in adherence-activated mononuclear phagocyte cultures. 2D-Abeta-WIB revealed that the proportion of Abeta(1-40) decreased significantly to 50.2+/-5.4% (n=10) of Abeta(total) compared to 65.9+/-5.6% (n=7) in non-adherent cultures (p<0.0001, t=5.82). Abeta(1-42) accounted for only 3.0+/-2.1% of Abeta(total) and its proportion did not change significantly upon adherence (2.8+/-0.5% of Abeta(total)). In adherence-activated cultures we detected pronounced shifts in the fractional pattern of released Abeta peptides in favour of N-truncated species. The second most prominent Abeta peptide accounted for as much as 12.7+/-3.0% of Abeta(total) (2.0+/-1.2% in non-adherent cultures; p<0.0001, t=9.00) and was identified as Abeta(2-40) by comigration with a synthetic peptide and by N-terminal-specific antibodies. A strong increase of a further Abeta immunoreactive spot migrating at pI 5.45 was observed. It accounted for 9.2+/-1.7% of Abeta(total) as compared to 1.0+/-0.9% in non-adherent cultures (p<0.0001, t=11.61) and presumably represented a variant of Abeta(2-40) as determined by C-terminal Abeta(40)-specific immunoprecipitation and N-terminal-specific immunodetection. Thus, mononuclear phagocytes might be one source of the N-truncated Abeta peptides regularly found in human plasma and are less likely to contribute substantially to plasma Abeta(1-42).

Czirr E, Cottrell BA, Leuchtenberger S, Kukar T, Ladd TB, Esselmann H, Paul S, Schubenel R, Torpey JW, Pietrzik CU, Golde TE, Wiltfang J, Baumann K, Koo EH, Weggen S. · Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine-University, D-40225 Duesseldorf, Germany. · J Biol Chem. · Pubmed #18426795 links to  free full text

Abstract: Proteolytic processing of the amyloid precursor protein by beta- and gamma-secretase generates the amyloid-beta (Abeta) peptides, which are principal drug targets in Alzheimer disease therapeutics. gamma-Secretase has imprecise cleavage specificity and generates the most abundant Abeta40 and Abeta42 species together with longer and shorter peptides such as Abeta38. Several mechanisms could explain the production of multiple Abeta peptides by gamma-secretase, including sequential processing of longer into shorter Abeta peptides. A novel class of gamma-secretase modulators (GSMs) that includes some non-steroidal anti-inflammatory drugs has been shown to selectively lower Abeta42 levels without a change in Abeta40 levels. A signature of GSMs is the concomitant increase in shorter Abeta peptides, such as Abeta38, leading to the suggestion that generation of Abeta42 and Abeta38 peptide species by gamma-secretase is coordinately regulated. However, no evidence for or against such a precursor-product relationship has been provided. We have previously shown that stable overexpression of aggressive presenilin-1 (PS1) mutations associated with early-onset familial Alzheimer disease attenuated the cellular response to GSMs, resulting in greatly diminished Abeta42 reductions as compared with wild type PS1. We have now used this model system to investigate whether Abeta38 production would be similarly affected indicating coupled generation of Abeta42 and Abeta38 peptides. Surprisingly, treatment with the GSM sulindac sulfide increased Abeta38 production to similar levels in four different PS1 mutant cell lines as compared with wild type PS1 cells. This was confirmed with the structurally divergent GSMs ibuprofen and indomethacin. Mass spectrometry analysis and high resolution urea gel electrophoresis further demonstrated that sulindac sulfide did not induce detectable compensatory changes in levels of other Abeta peptide species. These data provide evidence that Abeta42 and Abeta38 species can be independently generated by gamma-secretase and argue against a precursor-product relationship between these peptides.

Maler JM, Klafki HW, Paul S, Spitzer P, Groemer TW, Henkel AW, Esselmann H, Lewczuk P, Kornhuber J, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Proteomics. · Pubmed #17924594 No free full text.

Abstract: The detailed analysis of beta-amyloid (Abeta) peptides in human plasma is still hampered by the limited sensitivity of available mass spectrometric methods and the lack of appropiate ELISAs to measure Abeta peptides other than Abeta(1-38), Abeta(1-40), and Abeta(1-42). By combining high-yield Abeta immuno- precipitation (IP), IEF, and urea-based Abeta-SDS-PAGE-immunoblot, at least 30 Abeta-immuno-reactive spots were detected in human plasma samples as small as 1.6 mL. This approach clearly resolved Abeta peptides Abeta(1-40), Abeta(1-42), Abeta(1-37), Abeta(1-38), Abeta(1-39), the N-truncated Abeta(2-40), Abeta(2-42), and, for the first time, also Abeta(1-41). Relative quantification indicated that Abeta(1-40) and Abeta(1-42) accounted for less than 60% of the total amount of Abeta peptides in plasma. All other Abeta peptides appear to be either C-terminally or N-terminally truncated forms or as yet uncharacterized Abeta species which migrated as trains of spots with distinct pIs. The Abeta pattern found in cerebrospinal fluid (CSF) was substantially less complex. This sensitive method (2-D Abeta-WIB) might help clarifying the origin of distinct Abeta species from different tissues, cell types, or intracellular pools as well as their amyloidogenicity. It might further help identifying plasma Abeta species suitable as biomarkers for the diagnosis of Alzheimer's disease (AD).

Bibl M, Esselmann H, Mollenhauer B, Weniger G, Welge V, Liess M, Lewczuk P, Otto M, Schulz JB, Trenkwalder C, Kornhuber J, Wiltfang J. · Department of Psychiatry University of Goettingen, von-Siebold-Str, Goettingen, Germany. · J Neurochem. · Pubmed #17662050 No free full text.

Abstract: Blood-based tests for the differential diagnosis of Alzheimer's disease (AD) are under intensive investigation and have shown promising results with regard to Abeta40 and Abeta42 peptide species in incipient AD. Moreover, plasma Abeta40 was suggested as an independent cerebrovascular risk factor candidate. These considerations prompted us to analyse a total of 72 plasma samples in vascular dementias (VAD, n = 15), AD with cerebrovascular disease (AD with CVD, n = 7), AD (n = 15), Parkinson's disease and Parkinson's disease dementia (PD/PDD, n = 20) and 15 patients with depression that served as controls (DC) for distinct plasma amyloid-beta (Abeta) peptide patterns. For the analysis of plasma we used immunoprecipitation followed by the quantitative Abeta-SDS-PAGE/immunoblot. For comparison, CSF tau and Abeta1-42 analyses were performed. The major outcome was an increase in Abeta1-40 in plasma of VAD paralleled by a decrease in the ratio of Abeta1-38/Abeta1-40. The ratio Abeta1-38/Abeta1-40 in plasma enabled contrasts of beyond 85% and 80% for discriminating VAD from DC and all other patients, respectively. In CSF, we confirmed the typical CSF biomarker constellation of increased tau and diminished Abeta1-42 levels for AD. The diagnostic accuracy of plasma Abeta1-38/Abeta1-40 for VAD resembled the accuracy of CSF biomarkers for AD. From the presented results, we consider the ratio of plasma Abeta1-38/Abeta1-40 peptides to be a blood-based biomarker candidate for VAD.

Bibl M, Mollenhauer B, Lewczuk P, Esselmann H, Wolf S, Trenkwalder C, Otto M, Stiens G, Rüther E, Kornhuber J, Wiltfang J. · Department of Psychiatry, University of Goettingen, Goettingen, Germany. · Mol Psychiatry. · Pubmed #17339876 No free full text.

Abstract: Biomarkers for differential diagnosis of the three most frequent degenerative forms of dementia, Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementias (FTD), are currently under intensive investigation, but disease-specific biomarkers for FTD and DLB are still lacking. We analyzed 303 cerebrospinal fluid (CSF) samples of 71 AD, 32 DLB and 36 FTD patients in comparison to 93 various other dementias (OD), 20 peripheral neurologic disease (PND) controls, 25 neurodegenerative disorders without dementia (ND) and 26 depressive cognitive complainers (DCC) for distinct CSF amyloid-beta (Abeta) peptide patterns, using the quantitative Abeta-SDS-PAGE/immunoblot. Additionally, the novel electrochemiluminescence technique (MSD) was used to validate the measures on Abeta1-38. The main outcome measures were a striking decrease of Abeta1-42 in AD (P=7.4 x 10(-19)), and most interestingly a pronounced decrease of Abeta1-38 in FTD (P=9.6 x 10(-7)). Moreover, a novel peptide that most probably represents an oxidized alpha-helical form of Abeta1-40 (Abeta1-40(ox)) displayed a highly significant increase in DLB (P=3.7 x 10(-3)) as compared to non-demented disease controls. The overall diagnostic accuracy of percentage Abeta peptide abundances (Abeta1-X%) was clearly superior to absolute CSF Abeta levels. Abeta1-42% and Abeta1-38% enabled contrasts of 85% or beyond to distinguish AD and FTD, respectively, from all other investigated subjects. Abeta1-40(ox)% yielded a diagnostic sensitivity and specificity of 88 and 73% for the detection of DLB among all other investigated patients. We found a strong correlation between Abeta1-38 levels as measured by the Abeta-SDS-PAGE/immunoblot and MSD, respectively. CSF Abeta peptides may reflect disease-specific impact of distinct neurodegenerative processes on Abeta peptide metabolism and represent a potential diagnostic biomarker for AD, FTD and DLB.

Henkel AW, Dittrich PS, Groemer TW, Lemke EA, Klingauf J, Klafki HW, Lewczuk P, Esselmann H, Schwille P, Kornhuber J, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Mol Psychiatry. · Pubmed #17279093 No free full text.

Abstract: The diagnostic potential of large A beta-peptide binding particles (LAPs) in the cerebrospinal fluid (CSF) of Alzheimer's dementia (AD) patients and non-AD controls (nAD) was evaluated. LAPs were detected by confocal spectroscopy in both groups with high inter-individual variation in number. Molecular imaging by confocal microscopy revealed that LAPs are heterogeneous superaggregates that could be subdivided morphologically into four main types (LAP 1-4). LAP-4 type, resembling a 'large chain of pearls', was detected in 42.1% of all nAD controls but it was virtually absent in AD patients. LAP-4 type could be selectively removed by protein A beads, a clear indication that it contained immunoglobulins in addition to beta-amyloid peptides (A beta 1-42). We observed a close correlation between LAPs and immunoglobulin G (IgG) concentration in CSF in controls but not in AD patients. Double labeling of LAPs with anti-A beta and anti-IgG antibodies confirmed that LAP-4 type consisted of A beta and IgG aggregates. Our results assign a central role to the immune system in regulating A beta1-42 homeostasis by clustering this peptide in immunocomplexes.

Wiltfang J, Esselmann H, Bibl M, Hüll M, Hampel H, Kessler H, Frölich L, Schröder J, Peters O, Jessen F, Luckhaus C, Perneczky R, Jahn H, Fiszer M, Maler JM, Zimmermann R, Bruckmoser R, Kornhuber J, Lewczuk P. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · J Neurochem. · Pubmed #17254013 No free full text.

Abstract: Neurochemical dementia diagnostics (NDD) can significantly improve the clinically based categorization of patients with early dementia disorders, and the cerebrospinal fluid (CSF) concentrations of amyloid beta peptides ending at the amino acid position of 42 (A beta x-42 and A beta 1-42) are widely accepted biomarkers of Alzheimer's disease (AD). However, in subjects with constitutively high- or low-CSF concentrations of total A beta peptides (tA beta), the NDD interpretation might lead to erroneous conclusions as these biomarkers seem to correlate better with the total A beta load than with the pathological status of a given patient in such cases. In this multicenter study, we found significantly increased CSF concentrations of phosphorylated Tau (pTau181) and total Tau in the group of subjects with high CSF A beta x-40 concentrations and decreased A beta x-42/x-40 concentration ratio compared with the group of subjects with low CSF A beta x-40 and normal A beta ratio (p<0.001 in both cases). Furthermore, we observed significantly decreased A beta ratio (p<0.01) in the group of subjects with APOE epsilon 4 allele compared with the group of subjects without this allele. Surprisingly, patients with low-A beta x-40 and the decreased A beta ratio characterized with decreased pTau181 (p<0.05), and unaltered total Tau compared with the subjects with high A beta x-40 and the A beta ratio in the normal range. We conclude that the amyloid beta concentration ratio should replace the 'raw' concentrations of corresponding A beta peptides to improve reliability of the neurochemical dementia diagnosis.

Bibl M, Mollenhauer B, Wolf S, Esselmann H, Lewczuk P, Kornhuber J, Wiltfang J. · Department of Psychiatry, University of Goettingen, Goettingen, Germany. · J Neural Transm. · Pubmed #17245538 No free full text.

Abstract: Cerebrospinal fluid (CSF) carboxyterminally truncated amyloid-beta (Abeta) peptides, Abeta1-42 and tau protein were evaluated in 30 patients with frontotemporal lobe degenerations (FTLD), 30 Alzheimer's disease (AD) patients and 30 non-demented disease controls (NDC) by Abeta-SDS-PAGE/immunoblot as well as commercial ELISAs for Abeta1-42 and total tau. FTLD displayed a significant drop of Abeta1-37 (p = 2.7 x 10(-4)), Abeta1-38 (p = 4.2 x 10(-5)) and Abeta1-42 (p = 3.3 x 10(-4)). Abeta1-42 was selectively decreased in AD (p = 8.5 x 10(-10)). Decreased Abeta1-38 enabled contrasts of beyond 85% to distinguish FTLD from AD and NDC patients, alone or in combination. Accordingly, low CSF Abeta1-37 and Abeta1-38 represent a biomarker candidate for FTLD and may reflect disease-specific changes of APP metabolism. Further validation should be carried out on dementias other than AD, diagnostically relevant control groups without dementia and without any evident affection of the central nervous system and subgroups of FTLD. Moreover, independent methods of measurement should be applied to CSF Abeta1-38.

Lewczuk P, Kornhuber J, Vanderstichele H, Vanmechelen E, Esselmann H, Bibl M, Wolf S, Otto M, Reulbach U, Kölsch H, Jessen F, Schröder J, Schönknecht P, Hampel H, Peters O, Weimer E, Perneczky R, Jahn H, Luckhaus C, Lamla U, Supprian T, Maler JM, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Neurobiol Aging. · Pubmed #17239996 No free full text.

Abstract: In this report we evaluated the clinical performance of APOE genotyping and three protein biomarkers (total tau, beta-amyloid(1-42), and tau phosphorylated at threonine 181) in a prospective multicenter study using the INNO-BIA AlzBio3 assay applied on Luminex platform. Concentration of biomarkers of Alzheimer's disease in cerebrospinal fluid (CSF) was measured with multiplexing technology (n=223), and compared to the results of ELISA assays in patients with early dementias or mild cognitive impairment (MCI) collected at 12 gerontopsychiatric university departments, and APOE genotyping was performed. Concentrations of Abeta(1-42) were statistically significantly lower in MCI-AD subjects compared to MCI-O, and significantly lower in D-AD patients compared to MCI-O. P-tau(181P) concentrations were significantly higher in MCI-AD patients compared to MCI-O, and significantly higher in D-AD patients compared to MCI-O. The total tau concentrations in MCI-AD patients were significantly higher compared to MCI-O, and higher in D-AD compared to MCI-O, moreover, the concentration of total tau was significantly higher in D-AD compared to MCI-AD patients. For the differential diagnosis between D-AD and D-O, the optimal cutoff concentration of Abeta(1-42) was 197.7 pg/mL, and that for P-tau(181P) was 47.9 pg/mL. These cutoff values were also applied to discriminate between MCI-AD and MCI-O subjects. Simultaneous measurement of the biomarkers significantly improves management of the samples and quality control of the assays' performance.

Lewczuk P, Beck G, Ganslandt O, Esselmann H, Deisenhammer F, Regeniter A, Petereit HF, Tumani H, Gerritzen A, Oschmann P, Schröder J, Schönknecht P, Zimmermann K, Hampel H, Bürger K, Otto M, Haustein S, Herzog K, Dannenberg R, Wurster U, Bibl M, Maler JM, Reubach U, Kornhuber J, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Neurosci Lett. · Pubmed #17045397 No free full text.

Abstract: Currently, neurochemical dementia diagnostics (NDD) are increasingly entering routine clinical neurochemistry, offering improved early and differential diagnosis of dementias. However, there is an obvious lack of standardization in pre-analytical sample handling and systematic quality surveys. Therefore, in this study, 14 laboratories in Germany, Austria, and Switzerland were given aliquots of a human cerebrospinal fluid (CSF) sample, and were asked to measure Alzheimer's disease (AD) biomarkers (amyloid beta (Abeta) peptides, total Tau protein, and phosphorylated Tau protein (P-tau(181P))) according to their routine protocols. Results: The inter-laboratory coefficients of variation of the results obtained by the laboratories participating in this study were in the range of 20-30%. Although the results of this quality control survey are promising, the quality of measurements has to be further optimized.

Bibl M, Mollenhauer B, Esselmann H, Lewczuk P, Trenkwalder C, Brechlin P, Rüther E, Kornhuber J, Otto M, Wiltfang J. · Department of Psychiatry, University of Goettingen, Goettingen, Germany. · J Neural Transm. · Pubmed #16906356 No free full text.

Abstract: Differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) is often crucial. CSF Tau protein and Amyloid-beta (A beta) peptides have shown diagnostic value for the diagnosis of AD, but discrimination from DLB was poor.Herein, we investigate CSF of 18 patients with probable AD, 25 with probable DLB and 14 non-demented disease controls (NDC) by A beta-SDS-PAGE/immunoblot and commercially available ELISAs for A beta1-42 and tau. CSF A beta peptide patterns and tau exhibited disease specific alterations among AD and DLB. The ratio of A beta1-42 to A beta1-38 and A beta1-42 to A beta1-37, respectively, in combination with absolute tau, yielded a sensitivity and specificity of 100 and 92%, respectively. We conclude that CSF A beta peptide patterns and tau levels reflect disease-specific pathophysiological pathways of these dementias as distinct neurochemical phenotypes. Combined evaluation of these biomarkers provides a reasonable accuracy for differential diagnosis of AD and DLB.

Bibl M, Mollenhauer B, Esselmann H, Lewczuk P, Klafki HW, Sparbier K, Smirnov A, Cepek L, Trenkwalder C, Rüther E, Kornhuber J, Otto M, Wiltfang J. · Department of Psychiatry, University of Goettingen, Goettingen, Germany. · Brain. · Pubmed #16600985 links to  free full text

Abstract: As the differential diagnosis of dementias based on established clinical criteria is often difficult, biomarkers for applicable diagnostic testing are currently under intensive investigation. Amyloid plaques deposited in the brain of patients suffering from Alzheimer's disease, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) mainly consist of carboxy-terminally elongated forms of amyloid-beta (Abeta) peptides, such as Abeta1-42. Absolute Abeta1-42 levels in CSF have shown diagnostic value for the diagnosis of Alzheimer's disease, but the discrimination among Alzheimer's disease, DLB and PDD was poor. A recently established quantitative urea-based Abeta-sodium-dodecylsulphate-polyacrylamide-gel-electrophoresis with Western immunoblot (Abeta-SDS-PAGE/immunoblot) revealed a highly conserved Abeta peptide pattern of the carboxy-terminally truncated Abeta peptides 1-37, 1-38, 1-39 in addition to 1-40 and 1-42 in human CSF. We used the Abeta-SDS-PAGE/immunoblot to investigate the CSF of 23 patients with Alzheimer's disease, 21 with DLB, 21 with PDD and 23 non-demented disease controls (NDC) for disease-specific alterations of the Abeta peptide patterns in its absolute and relative quantities. The diagnostic groups were matched for age and severity of dementia. The present study is the first attempt to evaluate the meaning of Abeta peptide patterns in CSF for differential diagnosis of the three neurodegenerative diseases--Alzheimer's disease, DLB and PDD. The Abeta peptide patterns displayed disease-specific variations and the ratio of the differentially altered Abeta1-42 to the Abeta1-37 levels subsequently discriminated all diagnostic groups from each other at a highly significant level, except DLB from PDD. Additionally, a novel peptide with Abeta-like immunoreactivity was observed constantly in the CSF of all 88 investigated patients. The pronounced percentage increase of this peptide in DLB allowed a highly significant discrimination from PDD. Using a cut-off point of 0.954%, this marker yielded a diagnostic sensitivity and specificity of 81 and 71%, respectively. From several lines of indication, we consider this peptide to represent an oxidized alpha-helical form of Abeta1-40 (Abeta1-40*). The increased abundance of Abeta1-40* probably reflects a disease-specific alteration of the Abeta1-40 metabolism in DLB. We conclude that Abeta peptide patterns reflect disease-specific pathophysiological pathways of different dementia syndromes as distinct neurochemical phenotypes. Although Abeta peptide patterns failed to fulfil the requirements for a sole biomarker, their combined evaluation with other biomarkers is promising in neurochemical dementia diagnosis. It is noteworthy that DLB and PDD exhibit distinct clinical temporal courses, despite their similar neuropathological appearance. Their distinct molecular phenotypes support the view of different pathophysiological pathways for each of these neurodegenerative diseases.

Lewczuk P, Esselmann H, Bibl M, Paul S, Svitek J, Miertschischk J, Meyrer R, Smirnov A, Maler JM, Klein C, Otto M, Bleich S, Sperling W, Kornhuber J, Rüther E, Wiltfang J. · Department of Psychiatry and Psychotherapy, Molecular Neurobiology Lab, University of Erlangen-Nuernberg, Erlangen, Germany. · Electrophoresis. · Pubmed #15490456 No free full text.

Abstract: In this prospective study, for the first time we have separated and quantified amyloid beta (Abeta) peptides in the plasma of patients with Alzheimer's disease (AD, n = 8) and age- and environment-matched healthy controls (n = 9) with urea-based Abeta-sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)/immunoblot. In addition to the Abeta peptides 1-37/38/39/40/42, which we recently identified as regular constituents of human cerebrospinal fluid (CSF), we have observed a novel electrophoretic band migrating slightly cathodically to Abeta1-42. Since a standard peptide with the amino acid sequence Abeta2-40 migrates in the same position, we hypothesize that this plasma-specific band may correspond to Abeta2-40. The concentration of Abeta peptides in the plasma has been approximately 100-fold lower compared to the CSF. Interestingly, the concentration of the two shortest peptides and the longest one of these considered here (i.e., Abeta1-37/38/42) have increased significantly when the samples have been frozen at -80 degrees C before immunoprecipitation, while the 'middle-length' peptides (i.e., Abeta1-39/40) have not been affected by this procedure. We have not observed significant differences of the Abeta peptides concentrations between AD and control subjects. Our method can be used to investigate the significance of plasma Abeta peptides in neurodegenerative disorders, and to monitor the efficiency of drugs with beta/gamma-secretase inhibitory potency.

Steinacker P, Mollenhauer B, Bibl M, Cepek L, Esselmann H, Brechlin P, Lewczuk P, Poser S, Kretzschmar HA, Wiltfang J, Trenkwalder C, Otto M. · Department of Neurology, University Hospital, Robert-Koch-Str. 40, 37075 Goettingen, Germany. · Neurosci Lett. · Pubmed #15489013 No free full text.

Abstract: The diagnosis of neurodegenerative diseases with dementias requires several different test approaches and often remains uncertain. Using a proteomic approach it was shown in nine patients that heart fatty acid binding protein (H-FABP) might be a biomarker for Creutzfeldt-Jakob disease (CJD). The aim of our study was to evaluate whether H-FABP is a biomarker for the differential diagnosis of dementias. Therefore we measured H-FABP in cerebrospinal fluid (CSF) and serum of patients having CJD, dementia with Lewy-bodies (DLB), Alzheimer's disease (AD) and in non-demented control (NDC) patients. H-FABP levels in CSF and serum of CJD patients are increased compared to non-demented controls. Levels of H-FABP were significantly higher in CJD patients compared to AD and DLB in CSF. However, discrimination between CJD and AD was not possible in serum. Interestingly, highest levels of H-FABP were found in serum of DLB patients. Our results suggest that H-FABP might be a useful biomarker for the differentiation between the dementias examined if levels in CSF and serum are determined in parallel.

Bibl M, Esselmann H, Otto M, Lewczuk P, Cepek L, Rüther E, Kornhuber J, Wiltfang J. · Department of Psychiatry, University of Göttingen, Göttingen, Germany. · Electrophoresis. · Pubmed #15349929 No free full text.

Abstract: A quantitative urea-based amyloid beta (Abeta)-sodium dodecyl sulfate-polyacrylamide gel electrophoresis with Western immunoblot (Abeta-SDS-PAGE/immunoblot) reveals highly conserved and disease-specific Abeta peptide patterns (Abeta 1-37, 1-38, 1-39, 1-40, 1-42) in Alzheimer's disease (AD) patients and nondemented controls. For further standardization of this method, we analyzed cerebrospinal fluid (CSF) of eight probable AD patients and seven nondemented controls using different preanalytical procedures for Abeta-SDS-PAGE/immunoblot and Abeta1-42-enzyme linked immunosorbent assay (ELISA). Both diagnostic groups were discriminated significantly by absolute levels of Abeta1-42 and ratios of Abeta1-42/40, 1-42/38, 1-42/39. Preanalytical freezing of CSF led to a highly significant loss of all Abeta peptide species. This effect was most pronounced for Abeta1-42 and completely prevented by SDS-heat denaturation prior to freezing. Prolonged storage of SDS-heat denatured CSF led to a selective loss of Abeta1-42 and impaired the discrimination of diagnostic groups as measured by Abeta-SDS-PAGE/immunoblot. Neither freezing nor storage significantly affected absolute Abeta1-42 levels as determined by Abeta1-42-ELISA, but both impaired the discrimination of diagnostic groups. Hence, we suggest immediate analysis of samples for Abeta1-42-ELISA, analysis after a short freezing interval for Abeta-SDS-PAGE/immunoblot, and avoidance of prolonged storage intervals. Remarkably, Abeta-SDS-PAGE/immunoblot measured threefold higher levels of Abeta1-42 in CSF than Abeta1-42-ELISA. In summary, our results indicate carrier-mediated epitope masking of Abeta1-42.

Lewczuk P, Esselmann H, Bibl M, Beck G, Maler JM, Otto M, Kornhuber J, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, 91054 Erlangen, Germany. · J Mol Neurosci. · Pubmed #15126697 No free full text.

Abstract: Cerebrospinal fluid (CSF) concentrations of total Tau and Tau phosphorylated at threonine (position 181 [pTau181]) were studied with ELISA in a group of carefully selected patients with a neurochemically supported diagnosis of Alzheimer's disease (AD, n = 9; age range, 51-89 yr) and in a group of sex- and age-matched nondemented controls (n = 9; age range, 52-81 yr). The concentration of both biomarkers is increased significantly in the AD group (total Tau, p < 0.0008; pTau181, p < 0.008). A significant correlation between CSF concentrations of both biomarkers is observed (R = 0.897; p < 0.001). Neither total Tau nor pTau181 correlates with age or degree of memory impairment, and only a tendency is observed between the concentrations of total Tau and Abeta42 in the CSF. Our results further confirm a possible role of pTau181 as a diagnostic tool in AD. The current literature regarding the physiological and pathological role of phosphorylated Tau proteins is reviewed, as well as the role of these proteins as promising biomarkers in the diagnosis of neurodegenerative disorders.

Lewczuk P, Esselmann H, Otto M, Maler JM, Henkel AW, Henkel MK, Eikenberg O, Antz C, Krause WR, Reulbach U, Kornhuber J, Wiltfang J. · Molecular Neurobiology Lab, Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. · Neurobiol Aging. · Pubmed #15123331 No free full text.

Abstract: Cerebrospinal fluid (CSF) concentrations of amyloid beta peptides ending at positions 42 and 40 (Abeta42 and Abeta40, respectively), and total tau (tTau) protein were measured by ELISA in order to compare their accuracy in discriminating patients with Alzheimer's disease (AD, n = 22), non-Alzheimer dementia (nAD, n = 11) and control subjects (CON, n=35). As compared to the other groups, the concentrations of Abeta42 and tTau were decreased (P<0.001) and increased (P<0.001) in AD, respectively, while Abeta40 did not differ significantly among the groups. Receiver operating characteristic (ROC) analysis was performed to define cut-off values for maximized sensitivity and specificity. For all groups compared the Abeta peptide ratio 42/40 classified more patients correctly, as compared to the concentration of Abeta42 alone: AD versus controls, 94 and 86.7%; AD versus nAD, 90 and 85% and AD versus nAD plus controls, 90.8 and 87%, respectively. The percentage of correctly classified patients was further improved when the Abeta ratio was combined with the analysis of the tTau concentration. Presence of the apolipoprotein E 4 allele, age or degree of mental disability did not significantly influence the parameters studied.